Malaria
Conditions
Brief summary
The RTS,S/AS02A vaccine (or GSK 257049 vaccine), GSK Biologicals' candidate Plasmodium falciparum (P. falciparum) malaria vaccine is being developed for the routine immunization of infants and children living in malaria endemic areas. The vaccine would offer protection against malaria disease due to the parasite P. falciparum. The vaccine would also provide protection against infection with hepatitis B virus (HBV). This phase IIb trial is being carried out following the demonstration of efficacy of the candidate malaria vaccine in children in Mozambique: there, the vaccine demonstrated approximately 30% efficacy against clinical episodes of malaria and approximately 58% efficacy against severe malaria disease. In this study, the children from Mozambique (NCT= NCT00197041) are followed-up to assess the safety, immunogenicity and efficacy of the candidate malaria vaccine for a two year period commencing 21 months after Dose 1. This protocol posting deals with objectives & outcome measures of the extension phase at year 2. During this extension study, no new subjects will be recruited and no vaccine will be administered. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007.
Interventions
IM injection in the deltoid muscle
BIOLOGICALEngerix™-B
IM injection in the deltoid muscle
BIOLOGICALHiberix®
IM injection in the deltoid muscle
BIOLOGICALPrevnar™
IM injection in the deltoid muscle
DRUGsulfadoxine-pyrimethamine
1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance
DRUGamodiaquine
1 dose orally per day for 3 days, 4 weeks prior to onset of surveillance
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
33 Months to 69 Months
Healthy volunteers
Yes
Inclusion criteria
* Completion of Visit 7, Month 21 of 104297 (NCT= NCT00197041). * Written informed consent obtained from the parent(s) or guardian(s) of the subject
Exclusion criteria
* Planned use of any investigational or non-registered drug or vaccine during the study period. * Simultaneous participation in any other clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Serious Adverse Events (SAEs) | Throughout the entire study period: from Month 21 to Month 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-hepatitis B (HBs) Antibody Concentrations. | At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | Concentrations are presented as geometric mean concentrations (GMCs), expressed in milli-international units per milliliter (mIU/mL). Anti-HBs antibody concentration levels were measured in blood samples from Cohort 2 only. |
| Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | Malaria infection by Plasmodium falciparum was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges. |
| Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 1 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges. |
| Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 2 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films in an unwell child brought for treatment with a history of fever (axillary temperature equal or above 37.5 degrees Celsius) within 24 hours or documented fever. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was performed on Cohort 1 subjects, with groups pooled across age ranges. |
| Anti-circumsporozoite Protein (CS) Antibody Concentrations. | At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | Concentrations for anti-CS antibodies are presented as Geometric Mean Concentrations (GMCs), expressed in Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off of 0.5 EL.U/mL. Subjects were pooled across age ranges for this outcome measure. |
| Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | PFMI was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The number of PFMI episodes (EPFMI) per person-year (pyr) was tabulated, using as unit EPFMI episode per pyr. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. |
| Number of Subjects With Anemia. | At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | Anemia was indicated by a hematocrit level (HL) below (\<) 25%. The numbers of subjects with HL below (\<) and above or equal (≥) 25 %, and with missing HL results were tabulated. In the tabulation below, the number of subjects falling into the HL ≥25% category corresponds to the number of subjects with anemia as asked per outcome. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. |
| Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia | At Months 33 (M33) and 45 (M45) (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study). | Subjects prevalent for P. falciparum parasitemia were defined as subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films.Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. |
| Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 | From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041 | PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 3 was defined as the presence of P. falciparum asexual parasitaemia above 15000 per microliter (µL) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges. |
Countries
Mozambique
Participant flow
Recruitment details
This current study NCT00323622, a follow-up (FU) study to the primary study NCT00197041, is aimed at vaccine safety assessment, and took place from Months 21 to 45 (Month 0 = Dose 1 administration of RTS,S/AS02A (GSK 257049) or comparator vaccine in the primary study).
Pre-assignment details
Once re-enrolled, subjects in this study were allocated to the same groups as in the NCT00197041 study, as well as the same cohorts, e. a. Cohorts 1 and 2 whose subjects were followed for analysis of, respectively, malaria infection and disease.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1-RTS,S/AS02A <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | 176 |
| Cohort 1-RTS,S/AS02A ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | 515 |
| Cohort 2-RTS,S/AS02A <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 in the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | 42 |
| Cohort 2-RTS,S/AS02A ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of RTS,S/AS02A (GSK 257049) vaccine at Months 0, 1 and 2 of the NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | 134 |
| Cohort 1-Prevnar-Hiberix <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | 159 |
| Cohort 1-Engerix-B ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. Subjects in this group are part of the Cohort 1 of the study, which was followed for analysis of malaria infection. | 528 |
| Cohort 2-Prevnar- Hiberix <24M Group Subjects, male and female, aged 12 to 24 months at first vaccination, were administered 2 doses of Prevnar™ vaccine at Months 0 and 2 and 1 dose of Hiberix® vaccine at Month 1 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | 43 |
| Cohort 2-Engerix-B ≥24M Group Subjects, male and female, aged between 24 and 48 months at first vaccination, were administered 3 doses of Engerix®-B vaccine at Months 0, 1 and 2 in the Primary NCT00197041 Study. Subjects in this group are part of the Cohort 2 of the study, which was followed for analysis of malaria disease. As Cohort 2 subjects, subjects in this group also received as part of the Primary NCT00197041 Study one dose of sulfadoxine-pyrimethamine and amodiaquine per day for 3 days 4 weeks prior to onset of surveillance, so as to clear any parasitemia. No additional dose of vaccine or drug was administered during this open follow-up NCT00323622 study. | 140 |
| Total | 1,737 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 | 0 | 7 | 0 | 0 | 2 |
| Overall Study | Other | 30 | 91 | 4 | 12 | 32 | 74 | 5 | 13 |
Baseline characteristics
| Characteristic | Cohort 1-RTS,S/AS02A <24M Group | Cohort 1-RTS,S/AS02A ≥24M Group | Cohort 2-RTS,S/AS02A <24M Group | Cohort 2-RTS,S/AS02A ≥24M Group | Cohort 1-Prevnar-Hiberix <24M Group | Cohort 1-Engerix-B ≥24M Group | Cohort 2-Prevnar- Hiberix <24M Group | Cohort 2-Engerix-B ≥24M Group | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 38 Months STANDARD_DEVIATION 4 | 62 Months STANDARD_DEVIATION 11 | 39 Months STANDARD_DEVIATION 4 | 62 Months STANDARD_DEVIATION 9 | 38 Months STANDARD_DEVIATION 3 | 62 Months STANDARD_DEVIATION 10 | 38 Months STANDARD_DEVIATION 3 | 61 Months STANDARD_DEVIATION 9 | 50.0 Months STANDARD_DEVIATION 6.6 |
| Gender Female | 85 Participants | 240 Participants | 19 Participants | 67 Participants | 79 Participants | 252 Participants | 16 Participants | 78 Participants | 836 Participants |
| Gender Male | 91 Participants | 275 Participants | 23 Participants | 67 Participants | 80 Participants | 276 Participants | 27 Participants | 62 Participants | 901 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 176 | 0 / 515 | 0 / 42 | 0 / 134 | 0 / 159 | 0 / 528 | 0 / 43 | 0 / 140 |
| serious Total, serious adverse events | 21 / 176 | 17 / 515 | 1 / 42 | 0 / 134 | 24 / 159 | 29 / 528 | 1 / 43 | 4 / 140 |
Outcome results
Primary
Number of Subjects With Serious Adverse Events (SAEs)
Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
Time frame: Throughout the entire study period: from Month 21 to Month 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).
Population: The analysis was performed on the Total Vaccinated cohort, which included all subjects vaccinated in the primary NCT00197041 study, and re- enrolled in this follow-up NCT 00323622 study, and for whom data were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 21 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 17 Subjects |
| Cohort 2-RTS,S/AS02A <24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 1 Subjects |
| Cohort 2-RTS,S/AS02A ≥24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 0 Subjects |
| Cohort 1-Prevnar-Hiberix <24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 24 Subjects |
| Cohort 1-Engerix-B ≥24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 29 Subjects |
| Cohort 2-Prevnar- Hiberix <24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 1 Subjects |
| Cohort 2-Engerix-B ≥24M Group | Number of Subjects With Serious Adverse Events (SAEs) | 4 Subjects |
Secondary
Anti-circumsporozoite Protein (CS) Antibody Concentrations.
Concentrations for anti-CS antibodies are presented as Geometric Mean Concentrations (GMCs), expressed in Enzyme-Linked Immunosorbent Assay (ELISA) units per milliliter (EL.U/mL). The cut-off of the assay was the seropositivity cut-off of 0.5 EL.U/mL. Subjects were pooled across age ranges for this outcome measure.
Time frame: At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).
Population: The Long Term According-to-Protocol (ATP) cohort for immunogenicity included all enrolled subjects from the primary study ATP cohort for immunogenicity who did not receive any additional vaccine dose containing circumsporozoite protein or hepatitis B antigens, with blood sample within protocol-defined time limits and available antibody measurements
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 33 [N = 490, 487, 149, 149] | 10.1 EL.U/mL |
| Cohort 1-RTS,S/AS02A <24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 45 [N = 452, 447, 150, 145] | 8.9 EL.U/mL |
| Cohort 1-RTS,S/AS02A ≥24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 45 [N = 452, 447, 150, 145] | NA EL.U/mL |
| Cohort 1-RTS,S/AS02A ≥24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 33 [N = 490, 487, 149, 149] | NA EL.U/mL |
| Cohort 2-RTS,S/AS02A <24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 33 [N = 490, 487, 149, 149] | 16.2 EL.U/mL |
| Cohort 2-RTS,S/AS02A <24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 45 [N = 452, 447, 150, 145] | 15.4 EL.U/mL |
| Cohort 2-RTS,S/AS02A ≥24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 33 [N = 490, 487, 149, 149] | 0.6 EL.U/mL |
| Cohort 2-RTS,S/AS02A ≥24M Group | Anti-circumsporozoite Protein (CS) Antibody Concentrations. | Month 45 [N = 452, 447, 150, 145] | 0.4 EL.U/mL |
Secondary
Anti-hepatitis B (HBs) Antibody Concentrations.
Concentrations are presented as geometric mean concentrations (GMCs), expressed in milli-international units per milliliter (mIU/mL). Anti-HBs antibody concentration levels were measured in blood samples from Cohort 2 only.
Time frame: At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).
Population: The Long Term According-to-Protocol (ATP) cohort for immunogenicity included all enrolled subjects from the primary study ATP cohort for immunogenicity who did not receive any additional vaccine dose containing circumsporozoite protein or hepatitis B antigens,with blood sample within protocol-defined time limits and available antibody measurements.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 33 [N = 33, 116, 34, 115] | 4008.6 mIU/mL |
| Cohort 1-RTS,S/AS02A <24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 45 [N = 35, 115, 32, 113] | 3323.8 mIU/mL |
| Cohort 1-RTS,S/AS02A ≥24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 45 [N = 35, 115, 32, 113] | 1557.0 mIU/mL |
| Cohort 1-RTS,S/AS02A ≥24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 33 [N = 33, 116, 34, 115] | 1842.5 mIU/mL |
| Cohort 2-RTS,S/AS02A <24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 33 [N = 33, 116, 34, 115] | 20.3 mIU/mL |
| Cohort 2-RTS,S/AS02A <24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 45 [N = 35, 115, 32, 113] | 26.6 mIU/mL |
| Cohort 2-RTS,S/AS02A ≥24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 33 [N = 33, 116, 34, 115] | 67.4 mIU/mL |
| Cohort 2-RTS,S/AS02A ≥24M Group | Anti-hepatitis B (HBs) Antibody Concentrations. | Month 45 [N = 35, 115, 32, 113] | 99.4 mIU/mL |
Secondary
Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI)
PFMI was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The number of PFMI episodes (EPFMI) per person-year (pyr) was tabulated, using as unit EPFMI episode per pyr. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time frame: From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) | EPFMI - PCD - M33-45 (N=638;629) | 99 EPFMI episode per pyr |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) | EPFMI - PCD - M21-33 (N=650;645) | 252 EPFMI episode per pyr |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) | EPFMI - PCD - M21-33 (N=650;645) | 291 EPFMI episode per pyr |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Primary Case Definition Clinical Episodes of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) | EPFMI - PCD - M33-45 (N=638;629) | 100 EPFMI episode per pyr |
Secondary
Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia
Subjects prevalent for P. falciparum parasitemia were defined as subjects with the presence of P. falciparum asexual parasitemia above 0 per microliter (µL) on Giemsa stained thick blood films.Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time frame: At Months 33 (M33) and 45 (M45) (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia | Subjects prevalent for parasitemia, M33[N=590,590] | 93 Subjects |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia | Subjects prevalent for parasitemia, M45[N=541,547] | 66 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia | Subjects prevalent for parasitemia, M33[N=590,590] | 121 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects Prevalent for Plasmodium Falciparum (P. Falciparum) Parasitemia | Subjects prevalent for parasitemia, M45[N=541,547] | 101 Subjects |
Secondary
Number of Subjects With Anemia.
Anemia was indicated by a hematocrit level (HL) below (\<) 25%. The numbers of subjects with HL below (\<) and above or equal (≥) 25 %, and with missing HL results were tabulated. In the tabulation below, the number of subjects falling into the HL ≥25% category corresponds to the number of subjects with anemia as asked per outcome. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time frame: At Months 33 and 45 (Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in the NCT00197041 study).
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Anemia. | HL ≥25%, Month 33 (N = 650, 645]) | 584 Subjects |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Anemia. | HL <25%, Month 45 (N = 638, 629) | 0 Subjects |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Anemia. | HL <25%, Month 33 (N = 650, 645) | 2 Subjects |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Anemia. | HL ≥25%, Month 45 (N = 638, 629) | 540 Subjects |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Anemia. | Missing Results, Month 33 (N = 650;645) | 64 Subjects |
| Cohort 1-RTS,S/AS02A <24M Group | Number of Subjects With Anemia. | Missing Results, Month 45 (N = 638;629) | 98 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Anemia. | Missing Results, Month 45 (N = 638;629) | 86 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Anemia. | HL <25%, Month 33 (N = 650, 645) | 2 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Anemia. | HL ≥25%, Month 33 (N = 650, 645]) | 593 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Anemia. | Missing Results, Month 33 (N = 650;645) | 50 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Anemia. | HL <25%, Month 45 (N = 638, 629) | 0 Subjects |
| Cohort 1-RTS,S/AS02A ≥24M Group | Number of Subjects With Anemia. | HL ≥25%, Month 45 (N = 638, 629) | 543 Subjects |
Secondary
Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition
Malaria infection by Plasmodium falciparum was detected by passive case detection. A symptomatic PFMI episode of Primary Case Definition (PCD) was defined as the presence of P. falciparum asexual parasitaemia above 2500 per µL on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius at the time of presentation) occurring in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges.
Time frame: From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition | RPFMI - PCD - M21-33 (N=650;645) | 0.330 n/PYAR |
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition | RPFMI - PCD - M33-45 (N=638;629) | 0.140 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition | RPFMI - PCD - M21-33 (N=650;645) | 0.375 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Clinical Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Primary Case Definition | RPFMI - PCD - M33-45 (N=638;629) | 0.149 n/PYAR |
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - GSK RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.0895% CI: [-2.5, 32.4]Regression, Cox
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.4395% CI: [-20.11, 35.18]Regression, Cox
Secondary
Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1
PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 1 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was solely performed on Cohort 1 subjects, with groups pooled across age ranges.
Time frame: From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 | RPFMI - SCD 1 - M21-33 (N=650;645) | 0.365 n/PYAR |
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 | RPFMI - SCD 1 - M33-45 (N=638;629) | 0.161 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 | RPFMI - SCD 1 - M21-33 (N=650;645) | 0.409 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 1 | RPFMI - SCD 1 - M33-45 (N=638;629) | 0.174 n/PYAR |
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.1195% CI: [-3.88, 30.28]Regression, Cox
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.3595% CI: [-16.27, 34.59]Regression, Cox
Secondary
Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2
PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 2 was defined as the presence of P. falciparum asexual parasitaemia (any level if parasitemia) on Giemsa stained thick blood films in an unwell child brought for treatment with a history of fever (axillary temperature equal or above 37.5 degrees Celsius) within 24 hours or documented fever. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was performed on Cohort 1 subjects, with groups pooled across age ranges.
Time frame: From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 | RPFMI - SCD 2 - M21-33 (N=650;645) | 0.540 n/PYAR |
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 | RPFMI - SCD 2 - M33-45 (N=638;629) | 0.260 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 | RPFMI - SCD 2 - M21-33 (N=650;645) | 0.630 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 2 | RPFMI - SCD 2 - M33-45 (N=638;629) | 0.270 n/PYAR |
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.0195% CI: [4.62, 31.93]Regression, Cox
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.5495% CI: [-17.37, 26.44]Regression, Cox
Secondary
Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3
PFMI was detected by passive case detection. Symptomatic PFMI of Secondary Case Definition (SCD) 3 was defined as the presence of P. falciparum asexual parasitaemia above 15000 per microliter (µL) on Giemsa stained thick blood films accompanied by fever (axillary temperature equal or above 37.5 degrees Celsius) in an unwell child brought for treatment to a healthcare facility. The time to first or only episode of symptomatic PFMI is expressed in terms of rate of first PFMI (RPFMI), that is, the number of PFMI events reported (n) over the period elapsed until the PFMI event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. Analysis for this outcome was performed on Cohort 1 subjects solely, with groups pooled across age ranges.
Time frame: From Month 21 to Month 33 (M21-33), and from Month 33 to Month 45 (M33-45). Month 0 = administration of Dose 1 of RTS,S/AS02A or comparator vaccine in study NCT00197041
Population: The analysis was performed on the According-to-Protocol cohort for efficacy, which included all evaluable subjects who had received the 3 doses of the RTS,S/AS02 or control vaccine(s) in the Primary NCT00197041, and with available data concerning efficacy measures starting 14 days post Dose 3 of RTS,S/AS02A or comparator vaccine(s).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 | RPFMI - SCD 3 - M21-33 (N=650;645) | 0.288 n/PYAR |
| Cohort 1-RTS,S/AS02A <24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 | RPFMI - SCD 3 - M33-45 (N=638;629) | 0.122 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 | RPFMI - SCD 3 - M21-33 (N=650;645) | 0.329 n/PYAR |
| Cohort 1-RTS,S/AS02A ≥24M Group | Time to First or Only Episode of Symptomatic Plasmodium Falciparum Malaria Infection (PFMI) of Secondary Case Definition 3 | RPFMI - SCD 3 - M33-45 (N=638;629) | 0.122 n/PYAR |
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 21-33 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.195% CI: [-3.75, 33.25]Regression, Cox
Comparison: The analysis aimed to compare rates of first PFMI (RPFMI) between groups over the Months 33-45 time period. Using RFPMI, a Cox model was used to evaluate vaccine efficacy (VE) allowing for adjustment factors. VE, point estimate of efficacy adjusted for covariates, was calculated as 1 - (minus) \[Hazard Ratio (HR) in Cohort 1 - RTS,S/AS02A Group \[HR1\]) divided by HR in Cohort 1 - Engerix-B/Prevnar-Hiberix Group \[HR2\])\], i. e. 1 - (HR1/HR2).p-value: 0.795% CI: [-31, 32.99]Regression, Cox